Highlights from Recent Cancer Literature
Journal: Cancer Research (2014)

Kleinman CL, Gerges N, Papillon-Cavanagh S, Sin-Chan P, Pramatarova A, Quang DA, et al. Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR. Nat Genet 2014;46:39–44.Kleinman and colleagues identify a recurrent fusion linking the promoter of a brain-specific gene, TTYH1, with the microRNA (miRNA) cluster C19MC in a rare childhood brain tumor, embryonal tumor with multilayered rosettes. Present in all 12 tumors analyzed, the fusion showed C19MC miRNA levels 150 to 1,000 times higher than in other supratentorial primitive neuroectodermal tumors. Based on seed sequence similarity between miRNAs in the C19MC and miR-290–295 cluster, analysis of 5,445 diverse tumor and normal samples revealed that C19MC miRNAs targeted retinoblastoma-like 2 (RBL2) transcripts, resulting in derepression of the de novo DNA methyltransferase DNMT3B and altered DNA methylation. These data identify abnormal regulation of a fetal neural developmental program as a potential tumorigenic mechanism.Handschick K, Beuerlein K, Jurida L, Bartkuhn M, Müller H, Soelch J, et al. Cyclin-dependent kinase 6 is a chromatin-bound cofactor for NF-κB-dependent gene expression. Mol Cell 2014;53:193–208.Handschick and colleagues demonstrate cell-cycle dysregulation as a driver of cytokine-triggered inflammatory gene expression in cancer. IL-1 or TNF-α stimulation induced a cell cycle–dependent increase in inflammatory gene expression, with knockdown of CDK6 decreasing IL-1–induced gene expression. Using ChIP-seq, they demonstrate that CDK6 could either stabilize NF-κB p65 (RELA) binding to DNA or regulate recruitment of p65 to the nucleus. CDK6 knockdown suppressed IL-1–induced p65 recruitment to the IL-8 promoter, decreased RNA-Pol II loading, and reduced IL8 mRNA expression. TAK1 (MAP3K7), an activator of MAPK and NF-κB, regulated cytokine-induced nuclear translocation and chromatin association of CDK6. These data link alterations between cell cycle and expression of inflammatory genes in cancer.Brastianos PK, Taylor-Weiner A, Manley PE, Jones RT, Dias-Santagata D5, Thorner AR, et al. Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet 2014;46:161–5.Craniopharyngiomas are termed “the most formidable of intracranial tumors” due to their suprasellar, surgically challenging location. Recurrent mutations in CTNBB1 drive adamantinomatous variants. To identify molecular mechanisms in more commonly occurring papillary variants, Brastianos and colleagues performed whole-exome sequencing (n = 15) followed by targeted genotyping (n = 95). Mutations in BRAF (3 of 3 papillary craniopharyngiomas in discovery set; 34 of 36 samples in validation set) were exclusive to papillary tumors and uniformly present throughout neoplastic epithelial cells, confirming clonality for these mutations. The high prevalence and mutually exclusive nature of mutations in CTNBB1 and BRAF in two prevalent subtypes of craniopharyngiomas support their roles as drivers, with BRAF inhibitors immediately relevant to patients.Cheung KJ, Gabrielson E, Werb Z, Ewald AJ. Collective invasion in breast cancer requires a conserved Basal epithelial program. Cell 2013;155:1639–51.Cheung and colleagues used organoid cultures to model collective invasion, mediated by a cohesive multicellular unit. Epithelial cells with a K14 (KRT14)/p63high basal phenotype led the invasion out of organoids and were enriched at metastatic sites in vivo. Besides the K14/p63 requirement, the authors indicate that collective invasion proceeded without epithelial-to-mesenchymal transition (EMT), suggesting that different subpopulations in a tumor adopt either EMT or K14/p63high programs for dissemination. K14/p63high cells may produce factors that recruit macrophages in vivo, as collagen-I fibrils, previously shown to promote dissemination, stimulated collective invasion. The results from these studies suggest that plastic interconversion between epithelial and mesenchymal states facilitates invasion. If K14/p63high tumor cells are required to maintain metastases, then targeting these subpopulations might prove efficacious.Shern JF, Chen L Chmielecki J, Wei JS, Patidar R, Rosenberg M, et al. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov 2014;4:216–31.Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood. Alveolar rhabdomyosarcoma shows a common fusion between PAX3 or PAX7 and FOXO1 that is absent in embryonal rhabdomyosarcoma. These authors sequenced 147 tumors and found that tumors with PAX fusions (50/147) showed increased mutational load. Fusion-negative tumors showed increased aneuploidy and mutations in receptor tyrosine kinase and RAS/PIK3CA. LOH of 11p15 occurred in 50% of cases, with 12q and MYCN amplicons in fusion-positive cases. Mutations in FGFR signaling occurred in 88% of fusion-negative samples. A PAX fusion cDNA upregulated genes corresponding to fusion-negative tumors FGFR4, CCND2, and IGF2 and upregulated PAX3–FOXO1 targets. Rhabdomyosarcoma tumors thus utilize a common RTK/RAS/PIK3CA pathway driven via PAX fusion (alveolar tumors) or mutations that are downstream targets of the PAX fusion (embryonal tumors).Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.